EP3939978A1 - Forme cristalline d'un inhibiteur de phosphodiestérase, son procédé de préparation et son utilisation - Google Patents

Forme cristalline d'un inhibiteur de phosphodiestérase, son procédé de préparation et son utilisation Download PDF

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EP3939978A1
EP3939978A1 EP20774770.0A EP20774770A EP3939978A1 EP 3939978 A1 EP3939978 A1 EP 3939978A1 EP 20774770 A EP20774770 A EP 20774770A EP 3939978 A1 EP3939978 A1 EP 3939978A1
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crystal form
compound
formula
characteristic peaks
ray powder
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EP3939978A4 (fr
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Zhonghui WAN
Lin Li
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Transthera Sciences Nanjing Inc
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Transthera Sciences Nanjing Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention falls within the technical field of medicine, and in particular relates to a crystal form of a phosphodiesterase inhibitor, a preparation method therefor and the use thereof.
  • Phosphodiesterase 9 is an important member of the PDE family and has a very high selectivity for cGMP. Phosphodiesterase 9 inhibitors can be used to treat diseases with respect to cognitive impairment caused by central nervous system disorders, such as Alzheimer's disease and schizophrenia, and neurodegenerative disease of brain.
  • An object of the present invention is to provide a crystal form of a compound of formula (I) and a preparation method therefor.
  • the present invention provides a crystal form I of a compound as shown in formula (I): the crystal form I of a compound as shown in formula (I), 6-ethyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-diazanaphthal ene-3-carbonitrile, has an X-ray powder diffraction pattern comprising characteristic peaks at 7.3 ⁇ 0.2°, 13.6 ⁇ 0.2°, 14.5 ⁇ 0.2°, 18.0 ⁇ 0.2°, 19.1 ⁇ 0.2°, 22.0 ⁇ 0.2° and 23.4 ⁇ 0.2° 2 ⁇ , as determined by using Cu-K ⁇ radiation,
  • the X-ray powder diffraction pattern of the crystal form I of the compound as shown in formula (I) comprises characteristic peaks at 14.2 ⁇ 0.2°, 16.1 ⁇ 0.2°, 19.4 ⁇ 0.2° and 25.6 ⁇ 0.2° 2 ⁇ , as determined by using Cu-K ⁇ radiation.
  • the X-ray powder diffraction pattern of the crystal form I of the compound as shown in formula (I) comprises characteristic peaks at 15.1 ⁇ 0.2° and 17.6 ⁇ 0.2° 2 ⁇ , as determined by using Cu-K ⁇ radiation.
  • the crystal form I of the compound as shown in formula (I) exhibits an X-ray powder diffraction pattern as substantially depicted in Figure 1 when Cu-K ⁇ radiation is used.
  • the present invention further provides a method for preparing the crystal form I of the compound as shown in formula (I): the method comprises dissolving the compound of formula (I) in a single or mixed solvent, raising the temperature to reflux until complete dissolution, and slowly decreasing the temperature until the crystal form I is precipitated.
  • the single or mixed solvent is selected from: one of or a mixture of methanol, ethanol, isopropanol, toluene, acetone, tetrahydrofuran, dichloromethane, dichloroethane, ethyl acetate, acetonitrile, methyl tert-butyl ether, 2-methyltetrahydrofuran, dimethyl sulfoxide and water.
  • the single or mixed solvent is selected from: methanol, ethanol, isopropanol, toluene, acetone, tetrahydrofuran, water ⁇ ethanol, water ⁇ isopropanol, dichloromethane, ethyl acetate and acetonitrile.
  • the expression “decreasing the temperature” refers to decreasing the temperature to less than 30°C, preferably to room temperature.
  • room temperature refers to 15°C-25°C, or refers to 10°C-30°C based on Pharmacopoeia of the People's Republic of China.
  • the single or mixed solvent is used in an amount of 20-30 times the volume of the compound of formula (I).
  • the present invention further provides another method for preparing the crystal form I of the compound as shown in formula (I): the method comprises completely dissolving the compound of formula (I) in a single or mixed solvent, and volatilizing the single or mixed solvent until the system is saturated and the crystal form I is precipitated.
  • the single or mixed solvent is selected from: one of or a mixture of methanol, ethanol, isopropanol, toluene, acetone, tetrahydrofuran, dichloromethane, dichloroethane, ethyl acetate, acetonitrile, methyl tert-butyl ether, 2-methyltetrahydrofuran, dimethyl sulfoxide and water.
  • the single or mixed solvent is selected from: methanol, ethanol, isopropanol, toluene, acetone, tetrahydrofuran, water ⁇ ethanol, water ⁇ isopropanol, dichloromethane, ethyl acetate, acetonitrile, dichloromethane ⁇ acetone, dichloromethane ⁇ acetonitrile, dichloromethane ⁇ ethyl acetate, dichloromethane ⁇ methyl tert-butyl ether, dichloromethane ⁇ tetrahydrofuran, dichloromethane ⁇ ethanol, dichloromethane ⁇ isopropanol, dichloromethane ⁇ toluene, dichloromethane ⁇ water ⁇ ethanol, and dichloromethane ⁇ water ⁇ isopropanol.
  • the single solvent is selected from methanol, ethanol, isopropanol, toluene, acetone, tetrahydrofuran, dichloromethane, ethyl acetate and acetonitrile.
  • the mixed solvent is selected from a mixture of dichloromethane and acetone, acetonitrile, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, ethanol, isopropanol, toluene, water ⁇ ethanol and water ⁇ isopropanol, with a volume ratio of 1 : 0.5-3, preferably 1 : 1.5-3.
  • the single or mixed solvent is used in an amount of more than 30 times the volume of the compound of formula (I).
  • volatilizing may refer to natural volatilization, or volatilization promoted by heating to a certain temperature.
  • the present invention provides a crystal form II of a hydrochloride of a compound as shown in formula (I): the crystal form II of a hydrochloride of a compound as shown in formula (I), 6-ethyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-diazanaphthal ene-3-carbonitrile, has an X-ray powder diffraction pattern comprising characteristic peaks at 4.0 ⁇ 0.2°, 6.7 ⁇ 0.2°, 7.9 ⁇ 0.2°, 13.5 ⁇ 0.2°, 14.2 ⁇ 0.2°, 15.4 ⁇ 0.2°, 20.2 ⁇ 0.2° and 22.0 ⁇ 0.2° 2 ⁇ , as determined by using Cu-K ⁇ radiation.
  • the X-ray powder diffraction pattern of the crystal form II of the compound as shown in formula (I) comprises characteristic peaks at 10.2 ⁇ 0.2°, 13.8 ⁇ 0.2°, 14.6 ⁇ 0.2°, 26.40 ⁇ 0.2° and 26.80 ⁇ 0.2° 2 ⁇ , as determined by using Cu-K ⁇ radiation.
  • the crystal form II of the compound as shown in formula (I) exhibits an X-ray powder diffraction pattern as substantially depicted in Figure 6 when Cu-K ⁇ radiation is used.
  • the present invention further provides a method for preparing the crystal form II of the compound as shown in formula (I): the method comprises adding a single or mixed solvent to the hydrochloride of the compound of formula (I), heating the mixture until complete dissolution, and slowly cooling down the heated mixture until the crystal form II is precipitated;
  • the single or mixed solvent is selected from: one of or a mixture of methanol, ethanol, isopropanol and water; preferably, the single or mixed solvent is selected from methanol, ethanol, isopropanol, water ⁇ methanol, water ⁇ ethanol, and water ⁇ isopropanol.
  • cooling down refers to cooling down to room temperature.
  • room temperature refers to 15°C-25°C, or refers to 10°C-30°C based on Pharmacopoeia of the People's Republic of China.
  • the present invention provides a crystal form III of a hydrochloride of a compound as shown in formula (I): the crystal form III of a hydrochloride of a compound as shown in formula (I), 6-ethyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-diazanaphthal ene-3-carbonitrile, has an X-ray powder diffraction pattern comprising characteristic peaks at 5.2 ⁇ 0.2°, 6.4 ⁇ 0.2°, 15.3 ⁇ 0.2°, 18.6 ⁇ 0.2°, 22.0 ⁇ 0.2° and 26.4 ⁇ 0.2° 2 ⁇ , as determined by using Cu-K ⁇ radiation.
  • the X-ray powder diffraction pattern of the crystal form III of the compound as shown in formula (I) comprises characteristic peaks at 8.0 ⁇ 0.2°, 10.3 ⁇ 0.2°, 13.5 ⁇ 0.2° and 25.0 ⁇ 0.2° 2 ⁇ , as determined by using Cu-K ⁇ radiation.
  • the crystal form III of the compound as shown in formula (I) exhibits an X-ray powder diffraction pattern as substantially depicted in Figure 9 when Cu-K ⁇ radiation is used.
  • the present invention further provides a method for preparing the crystal form III of the compound as shown in formula (I): the method comprises adding a single or mixed solvent to the hydrochloride of the compound of formula (I), heating the mixture until complete dissolution, performing filtration while hot, and concentrating the filtrate until the crystal form III is precipitated.
  • the single or mixed solvent is selected from: one of or a mixture of acetonitrile, acetone, tetrahydrofuran and ethyl acetate.
  • the present invention provides a crystal form IV of a p-toluenesulfonate of a compound as shown in formula (I): the crystal form IV of a p-toluenesulfonate of a compound as shown in formula (I), 6-ethyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-diazanaphthal ene-3-carbonitrile, has an X-ray powder diffraction pattern comprising characteristic peaks at 5.8 ⁇ 0.2°, 7.8 ⁇ 0.2°, 9.3 ⁇ 0.2°, 11.3 ⁇ 0.2°, 13.7 ⁇ 0.2°, 14.8 ⁇ 0.2° and 15.7 ⁇ 0.2° 2 ⁇ , as determined by using Cu-K ⁇ radiation,
  • the X-ray powder diffraction pattern of the crystal form IV of the compound as shown in formula (I) comprises characteristic peaks at 17.1 ⁇ 0.2°, 18.7 ⁇ 0.2°, 20.0 ⁇ 0.2° and 22.4 ⁇ 0.2° 2 ⁇ , as determined by using Cu-K ⁇ radiation.
  • the crystal form IV of the compound as shown in formula (I) exhibits an X-ray powder diffraction pattern as substantially depicted in Figure 12 when Cu-K ⁇ radiation is used.
  • the present invention further provides a method for preparing the crystal form IV of the compound as shown in formula (I): the method comprises adding the compound of formula (I) to p-toluenesulfonic acid, heating the mixture until complete dissolution, and slowly decreasing the temperature until the crystal form IV is precipitated.
  • the expression “decreasing the temperature” refers to decreasing the temperature to less than 30°C, preferably to room temperature.
  • the expression “room temperature” preferably refers to 15°C-25°C, or 10°C-30°C based on Pharmacopoeia of the People's Republic of China.
  • the p-toluenesulfonic acid is used in an amount of 5-30 times the volume of the compound of formula (I).
  • the p-toluenesulfonic acid may be p-toluenesulfonic acid with different concentrations, or an aqueous solution of p-toluenesulfonic acid.
  • the present invention provides a crystal form V of a methanesulfonate of a compound as shown in formula (I): the crystal form V of a methanesulfonate of a compound as shown in formula (I), 6-ethyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-diazanaphthal ene-3-carbonitrile, has an X-ray powder diffraction pattern comprising characteristic peaks at 7.0 ⁇ 0.2°, 9.7 ⁇ 0.2°, 13.2 ⁇ 0.2°, 18.1 ⁇ 0.2°, 19.5 ⁇ 0.2°, 20.7 ⁇ 0.2° and 21.7 ⁇ 0.2° 2 ⁇ , as determined by using Cu-K ⁇ radiation.
  • the X-ray powder diffraction pattern of the crystal form V of the compound as shown in formula (I) comprises characteristic peaks at 16.9 ⁇ 0.2°, 18.6 ⁇ 0.2°, 19.1 ⁇ 0.2°, 20.2 ⁇ 0.2° and 28.0 ⁇ 0.2° 2 ⁇ , as determined by using Cu-K ⁇ radiation.
  • the crystal form V of the compound as shown in formula (I) exhibits an X-ray powder diffraction pattern as substantially depicted in Figure 13 when Cu-K ⁇ radiation is used.
  • the present invention further provides a method for preparing the crystal form V of the compound as shown in formula (I): the method comprises adding the compound of formula (I) to methanesulfonic acid, heating the mixture until complete dissolution, and then adding a solvent, subjecting the mixture to suction filtration, and drying the suction-filtered mixture to obtain V, wherein the solvent is methanol, ethanol or isopropanol.
  • the methanesulfonic acid is used in an amount of 5-30 times the volume of the compound of formula (I).
  • the methanesulfonic acid may be methanesulfonic acid with different concentrations, or an aqueous solution of methanesulfonic acid.
  • the present invention provides a crystal form VI of a sulfate of a compound as shown in formula (I): the crystal form VI of a sulfate of a compound as shown in formula (I), 6-ethyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-diazanaphthal ene-3-carbonitrile, has an X-ray powder diffraction pattern comprising characteristic peaks at 4.4 ⁇ 0.2°, 7.1 ⁇ 0.2°, 8.8 ⁇ 0.2°, 14.3 ⁇ 0.2°, 17.8 ⁇ 0.2°, 19.6 ⁇ 0.2° and 21.6 ⁇ 0.2° 2 ⁇ , as determined by using Cu-K ⁇ radiation,
  • the X-ray powder diffraction pattern of the crystal form VI of the compound as shown in formula (I) comprises characteristic peaks at 25.5 ⁇ 0.2° and 27.7 ⁇ 0.2 2 ⁇ , as determined by using Cu-K ⁇ radiation.
  • the crystal form VI of the compound as shown in formula (I) exhibits an X-ray powder diffraction pattern as substantially depicted in Figure 14 when Cu-K ⁇ radiation is used.
  • the present invention further provides a method for preparing the crystal form VI of the compound as shown in formula (I):
  • the expression “decreasing the temperature” refers to decreasing the temperature to less than 30°C, preferably to room temperature.
  • room temperature refers to 10°C-30°C, preferably 15°C-25°C.
  • the aqueous solution of sulfuric acid is used in an amount of 2-30 times, preferably 2-10 times, more preferably 4 times, 5 times and 6 times the volume of the compound of formula (I).
  • the single or mixed solvent is used in an amount of 5-60 times, preferably 5-50 times, more preferably 10 times, 15 times and 50 times the volume of the sulfate of the compound of formula (I).
  • the single or mixed solvent is selected from one of or a mixture of acetone, ethanol, methanol and tetrahydrofuran; preferably, the solvent is a single solvent; more preferably, the single solvent is selected from acetone, ethanol, methanol and tetrahydrofuran.
  • the present invention provides a crystal form VII of a sulfate of a compound as shown in formula (I): the crystal form VII of a sulfate of the compound as shown in formula (I), 6-ethyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-diazanaphthal ene-3-carbonitrile, is characterized by having an X-ray powder diffraction pattern comprising characteristic peaks at 7.1 ⁇ 0.2°, 13.6 ⁇ 0.2°, 14.5 ⁇ 0.2°, 18.0 ⁇ 0.2°, 19.0 ⁇ 0.2°, 22.0 ⁇ 0.2° and 23.4 ⁇ 0.2° 2 ⁇ , as determined by using Cu-K ⁇ radiation,
  • the X-ray powder diffraction pattern of the crystal form VII of the compound as shown in formula (I) comprises characteristic peaks at 15.0 ⁇ 0.2°, 16.1 ⁇ 0.2°, 17.4 ⁇ 0.2° and 19.4 ⁇ 0.2° 2 ⁇ , as determined by using Cu-K ⁇ radiation.
  • the crystal form VII of the compound as shown in formula (I) exhibits an X-ray powder diffraction pattern as substantially depicted in Figure 18 when Cu-K ⁇ radiation is used.
  • the present invention further provides a method for preparing the crystal form VII of the compound as shown in formula (I): the method comprises adding the sulfate of the compound of formula (I) to isopropanol, heating the mixture until complete dissolution, and slowly decreasing the temperature until the crystal form VII is precipitated.
  • the expression “decreasing the temperature” refers to decreasing the temperature to less than 30°C, preferably to room temperature.
  • room temperature refers to 10°C-30°C, preferably 15°C-25°C.
  • the isopropanol is used in an amount of 5-60 times, preferably 10-50 times, more preferably 30-50 times the volume of the crystal form VI.
  • the present invention further provides a pharmaceutical composition comprising the crystal form I, II, III, IV, V, VI or VII of the compound as shown in formula (I), and one or more second therapeutically active agents.
  • the present invention further provides a pharmaceutical preparation comprising the crystal form I, II, III, IV, V, VI or VII of the compound as shown in formula (I).
  • the pharmaceutical preparation may comprise one or more pharmaceutical carriers.
  • the pharmaceutical carrier of the present invention may be one or more solid or liquid fillers suitable for human use.
  • the pharmaceutical carrier preferably has sufficient purity and sufficiently low toxicity, and is compatible with the compound provided by the present invention without significantly reducing its efficacy.
  • the pharmaceutical carrier may be a filler, a binder, a disintegrant, a lubricant, an aqueous solvent, a non-aqueous solvent, etc.
  • the pharmaceutical preparation of the present invention can be made into any pharmaceutically acceptable dosage form, and a "therapeutically effective amount" of the crystal form I, II, III, IV, V, VI or VII of the compound of formula (I) as described above is administered in any suitable manner, such as orally, parenterally, rectally or pulmonarily, to a patient or subject in need of such treatment.
  • a "therapeutically effective amount" of the crystal form I, II, III, IV, V, VI or VII of the compound of formula (I) as described above is administered in any suitable manner, such as orally, parenterally, rectally or pulmonarily, to a patient or subject in need of such treatment.
  • the pharmaceutical preparation When used for oral administration, can be prepared into a tablet, a capsule, a pill, a granule, etc.
  • parenteral administration the pharmaceutical preparation can be prepared into an injection, a sterile powder for injection, etc.
  • the present invention further provides the use of the crystal form I, II, III, IV, V, VI or VII of the compound as shown in formula (I), or the pharmaceutical preparation or pharmaceutical composition comprising the crystal form I, II, III, IV, V, VI or VII in the manufactureof a medicament for treating or preventing PDE9-mediated diseases.
  • the PDE9-mediated related diseases comprise CNS diseases, and more specifically, comprise impairments associated with perception, attention, memory and learning, senile dementia, schizophrenia, age-related memory loss, vascular dementia, craniocerebral injury, stroke, post-stroke dementia, post-traumatic dementia, general attention deficit, attention deficit with learning and memory problems in children, Alzheimer's disease, Lewy body dementia, frontotemporal lobe degeneration dementia, cortical basal ganglionic degeneration dementia, amyotrophic lateral sclerosis disease, Huntington's disease, multiple sclerosis, thalamic degeneration, dementia in Creutzfeldt-Jakob disease, HIV dementia, schizophrenia, epilepsy, Korsakoff's psychosis, depression, bipolar affective disorder, etc.
  • the PDE9-mediated related diseases comprise CNS-related diseases, and more specifically, comprise sleep disorder, metabolic syndrome, obesity, diabetes, hyperglycemia, dyslipidemia, impaired glucose tolerance, etc.
  • the PDE9-mediated related diseases comprise heart diseases and blood diseases, and more specifically, comprise heart failure, anemia, sickle-cell disease, etc.
  • the present invention further provides the use of the crystal form I, II, III, IV, V, VI or VII of the compound as shown in formula (I), or the pharmaceutical preparation or the pharmaceutical composition comprising the crystal form I, II, IV, V, VI or VII in the treatment or prevention of PDE9-mediated related diseases.
  • the present invention further provides a method for treating or preventing PDE9-mediated related diseases, the method comprising administering to a patient in need thereof a therapeutically effective amount of the crystal form I, II, III, IV, V, VI or VII of the formula (I) as described above, or the pharmaceutical preparation or pharmaceutical composition comprising the crystal form I, II, III, IV, V, VI or VII.
  • room temperature in the present invention refers to the indoor temperature, which is usually 15°C-25°C, or refers to 10°C-30°C based on Pharmacopoeia of the People's Republic of China.
  • times the volume refers to the volume (ml) of a solvent required to dissolve 1 g of a substance; for example, if the volume of the solvent required to dissolve 1 g of the compound of formula (I) is 20 ml, it is called 20 times the volume.
  • therapeutically effective amount in the present invention refers to the amount of the aforementioned compound or the pharmaceutically acceptable salt and stereoisomer thereof, the composition or the pharmaceutical preparation that, when administered to a patient, can at least alleviate the symptoms of the patient's condition.
  • the actual amount comprising the "therapeutically effective amount” will vary according to various situations, including but not limited to the specific conditions being treated, the severity of the condition, the physical and health status of the patient, and the administration route. An appropriate amount can be readily determined by a skilled medical practitioner using methods known in the medical field.
  • the crystal forms of the present invention have excellent physicochemical properties and pharmaceutical stability, and also have a greater improvement in pharmacodynamic and pharmacokinetic properties, which are more conducive to the research on druggability.
  • Step 1 Synthesis of 6-chloro-2 H -pyrido[3,4- d ][1,3]oxazin-2,4(1 H )-dione
  • Triethylamine (35.182 g, 0.3478 mol, 2 eq) and ethyl cyanoacetate (19.665 g, 0.1738 mol) were added to the above-mentioned reaction liquid, and reacted at 150°C for 3 h; LC-MS monitoring showed that the reaction was complete, and then the reaction liquid was cooled down to room temperature and concentrated under reduced pressure; water (200 mL) was added, and the mixture was adjusted to pH 1 with hydrochloric acid (1 mol/L), stirred for 15 minutes, and filtered by suction; and the filter cake was washed twice with EA, and dried at 40°C to obtain a product as a light brick-red solid (25.655 g, yield: 66%).
  • 6-chloro-4-hydroxyl-2-oxo-1,2-dihydro-1,7-diazanaphthalene-3-carbonitrile (5.0 g, 0.0226 mol, 1 eq) and phosphorus oxychloride (15 mL) were added to a reaction flask; the reaction flask was put into an oil bath already heated to 100°C for reaction for about 6 min; and the solid started to dissolve slowly, and the color gradually deepened from light yellow.
  • Step 1 Synthesis of 6-chloro-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-diazanaphth alene-3-carbonitrile
  • Step 2 Synthesis of 4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-6-vinyl-1,2-dihydro-1,7-diazanaphthal ene-3-carbonitrile
  • Step 3 Synthesis of 6-ethyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-diazanaphthal ene-3-carbonitrile
  • the X-ray powder diffraction pattern of the crystal form I comprises characteristic peaks at 7.3 ⁇ 0.2°, 13.6 ⁇ 0.2°, 14.5 ⁇ 0.2°, 18.0 ⁇ 0.2°, 19.1 ⁇ 0.2°, 22.0 ⁇ 0.2° and 23.4 ⁇ 0.2° 2 ⁇ (°), comprises characteristic peaks at 14.2 ⁇ 0.2°, 16.1 ⁇ 0.2°, 19.4 ⁇ 0.2° and 25.6 ⁇ 0.2° 2 ⁇ (°), and further comprises characteristic peaks at 15.1 ⁇ 0.2° and 17.6 ⁇ 0.2° 2 ⁇ (°), as determined by using Cu-K ⁇ radiation.
  • XRPD analysis is as shown in Figure 1 .
  • the melting temperature as measured by a differential scanning calorimeter of the crystal form I is about 256°C-258°C, which is as shown in Figure 2 .
  • the X-ray powder diffraction pattern of the crystal form I comprises characteristic peaks at 7.3 ⁇ 0.2°, 13.6 ⁇ 0.2°, 14.5 ⁇ 0.2°, 18.0 ⁇ 0.2°, 19.1 ⁇ 0.2°, 22.0 ⁇ 0.2° and 23.4 ⁇ 0.2° 2 ⁇ (°), comprises characteristic peaks at 14.2 ⁇ 0.2°, 16.1 ⁇ 0.2°, 19.4 ⁇ 0.2° and 25.6 ⁇ 0.2° 2 ⁇ (°), and further comprises characteristic peaks at 15.1 ⁇ 0.2° and 17.6 ⁇ 0.2° 2 ⁇ (°), as determined by using Cu-K ⁇ radiation.
  • XRPD analysis is as shown in Figure 3 .
  • the X-ray powder diffraction pattern of the crystal form I comprises characteristic peaks at 7.3 ⁇ 0.2°, 13.6 ⁇ 0.2°, 14.5 ⁇ 0.2°, 18.0 ⁇ 0.2°, 19.1 ⁇ 0.2°, 22.0 ⁇ 0.2° and 23.4 ⁇ 0.2° 2 ⁇ (°), comprises characteristic peaks at 14.2 ⁇ 0.2°, 16.1 ⁇ 0.2°, 19.4 ⁇ 0.2° and 25.6 ⁇ 0.2° 2 ⁇ (°), and further comprises characteristic peaks at 15.1 ⁇ 0.2° and 17.6 ⁇ 0.2° 2 ⁇ (°), as determined by using Cu-K ⁇ radiation.
  • XRPD analysis is as shown in Figure 4 .
  • the X-ray powder diffraction pattern of the crystal form I comprises characteristic peaks at 7.3 ⁇ 0.2°, 13.6 ⁇ 0.2°, 14.5 ⁇ 0.2°, 18.0 ⁇ 0.2°, 19.1 ⁇ 0.2°, 22.0 ⁇ 0.2° and 23.4 ⁇ 0.2° 2 ⁇ (°), comprises characteristic peaks at 14.2 ⁇ 0.2°, 16.1 ⁇ 0.2°, 19.4 ⁇ 0.2° and 25.6 ⁇ 0.2° 2 ⁇ (°), and further comprises characteristic peaks at 15.1 ⁇ 0.2° and 17.6 ⁇ 0.2° 2 ⁇ (°), as determined by using Cu-K ⁇ radiation.
  • XRPD analysis is as shown in Figure 5 .
  • the X-ray powder diffraction pattern of the crystal form II comprises characteristic peaks at 4.0 ⁇ 0.2°, 6.7 ⁇ 0.2°, 7.9 ⁇ 0.2°, 13.5 ⁇ 0.2°, 14.2 ⁇ 0.2°, 15.4 ⁇ 0.2°, 20.2 ⁇ 0.2° and 22.0 ⁇ 0.2° 2 ⁇ (°), and further comprises characteristic peaks at 10.2 ⁇ 0.2°, 13.8 ⁇ 0.2°, 14.6 ⁇ 0.2°, 26.40 ⁇ 0.2° and 26.80 ⁇ 0.2° 2 ⁇ (°), as determined by using Cu-K ⁇ radiation.
  • XRPD analysis is as shown in Figure 6 .
  • the X-ray powder diffraction pattern of the crystal form II comprises characteristic peaks at 4.0 ⁇ 0.2°, 6.7 ⁇ 0.2°, 7.9 ⁇ 0.2°, 13.5 ⁇ 0.2°, 14.2 ⁇ 0.2°, 15.4 ⁇ 0.2°, 20.2 ⁇ 0.2° and 22.0 ⁇ 0.2° 2 ⁇ (°), and further comprises characteristic peaks at 10.2 ⁇ 0.2°, 13.8 ⁇ 0.2°, 14.6 ⁇ 0.2°, 26.40 ⁇ 0.2° and 26.80 ⁇ 0.2° 2 ⁇ (°), as determined by using Cu-K ⁇ radiation.
  • XRPD analysis is as shown in Figure 7 .
  • the X-ray powder diffraction pattern of the crystal form II comprises characteristic peaks at 4.0 ⁇ 0.2°, 6.7 ⁇ 0.2°, 7.9 ⁇ 0.2°, 13.5 ⁇ 0.2°, 14.2 ⁇ 0.2°, 15.4 ⁇ 0.2°, 20.2 ⁇ 0.2° and 22.0 ⁇ 0.2° 2 ⁇ (°), and further comprises characteristic peaks at 10.2 ⁇ 0.2°, 13.8 ⁇ 0.2°, 14.6 ⁇ 0.2°, 26.40 ⁇ 0.2° and 26.80 ⁇ 0.2° 2 ⁇ (°), as determined by using Cu-K ⁇ radiation.
  • XRPD analysis is as shown in Figure 8 .
  • Ethanol was added to 200 mg of the hydrochloride of the compound of formula (I); the mixture was heated to 60°C until complete dissolution, slowly cooled down under stirring for crystallization, and filtered by suction; and the filter cake was dried under reduced pressure at 40°C to obtain the crystal form II.
  • Acetonitrile was added to 200 mg of the hydrochloride of the compound of formula (I); the mixture was heated to reflux until most of the solids were dissolved, and filtered by suction while hot; the filtrate was concentrated under reduced pressure until a large number of solids were precipitated, and filtered by suction; and the filter cake was dried under reduced pressure at 40°C to obtain the crystal form III.
  • the X-ray powder diffraction pattern of the crystal form III comprises characteristic peaks at 5.2 ⁇ 0.2°, 6.4 ⁇ 0.2°, 15.3 ⁇ 0.2°, 18.6 ⁇ 0.2°, 22.0 ⁇ 0.2° and 26.4 ⁇ 0.2° 2 ⁇ (°), and further comprises characteristic peaks at 8.0 ⁇ 0.2°, 10.3 ⁇ 0.2°, 13.5 ⁇ 0.2° and 25.0 ⁇ 0.2° 2 ⁇ (°), as determined by using Cu-K ⁇ radiation.
  • XRPD analysis is as shown in Figure 9 .
  • Acetone was added to 200 mg of the hydrochloride of the compound of formula (I); the mixture was heated to 60°C until most of the solids were dissolved, and filtered by suction while hot; the filtrate was concentrated under reduced pressure until a large number of solids were precipitated, and filtered by suction; and the filter cake was dried under reduced pressure at 40°C to obtain the crystal form III.
  • Ethyl acetate was added to 200 mg of the hydrochloride of the compound of formula (I); the mixture was heated to 60°C until most of the solids were dissolved, and filtered by suction while hot; the filtrate was concentrated under reduced pressure until a large number of solids were precipitated, and filtered by suction; and the filter cake was dried under reduced pressure at 40°C to obtain the crystal form III.
  • the X-ray powder diffraction pattern of the crystal form III comprises characteristic peaks at 5.2 ⁇ 0.2°, 6.4 ⁇ 0.2°, 15.3 ⁇ 0.2°, 18.6 ⁇ 0.2°, 22.0 ⁇ 0.2° and 26.4 ⁇ 0.2° 2 ⁇ (°), and further comprises characteristic peaks at 8.0 ⁇ 0.2°, 10.3 ⁇ 0.2°, 13.5 ⁇ 0.2° and 25.0 ⁇ 0.2° 2 ⁇ (°), as determined by using Cu-K ⁇ radiation.
  • XRPD analysis is as shown in Figure 10 .
  • Tetrahydrofuran was added to 200 mg of the hydrochloride of the compound of formula (I); the mixture was heated to 60°C until most of the solids were dissolved, and filtered by suction while hot; the filtrate was concentrated under reduced pressure until a large number of solids were precipitated, and filtered by suction; and the filter cake was dried under reduced pressure at 40°C to obtain the crystal form III.
  • the X-ray powder diffraction pattern of the crystal form III comprises characteristic peaks at 5.2 ⁇ 0.2°, 6.4 ⁇ 0.2°, 15.3 ⁇ 0.2°, 18.6 ⁇ 0.2°, 22.0 ⁇ 0.2° and 26.4 ⁇ 0.2° 2 ⁇ (°), and further comprises characteristic peaks at 8.0 ⁇ 0.2°, 10.3 ⁇ 0.2°, 13.5 ⁇ 0.2° and 25.0 ⁇ 0.2° 2 ⁇ (°), as determined by using Cu-K ⁇ radiation.
  • XRPD analysis is as shown in Figure 11 .
  • the X-ray powder diffraction pattern of the crystal form IV comprises characteristic peaks at 5.8 ⁇ 0.2°, 7.8 ⁇ 0.2°, 9.3 ⁇ 0.2°, 11.3 ⁇ 0.2°, 13.7 ⁇ 0.2°, 14.8 ⁇ 0.2° and 15.7 ⁇ 0.2° 2 ⁇ (°), and further comprises characteristic peaks at 17.1 ⁇ 0.2°, 18.7 ⁇ 0.2°, 20.0 ⁇ 0.2° and 22.4 ⁇ 0.2° 2 ⁇ (°), as determined by using Cu-K ⁇ radiation.
  • XRPD analysis is as shown in Figure 12 .
  • the X-ray powder diffraction pattern of the crystal form V comprises characteristic peaks at 7.0 ⁇ 0.2°, 9.7 ⁇ 0.2°, 13.2 ⁇ 0.2°, 18.1 ⁇ 0.2°, 19.5 ⁇ 0.2°, 20.7 ⁇ 0.2° and 21.7 ⁇ 0.2° 2 ⁇ (°), and further comprises characteristic peaks at 16.9 ⁇ 0.2°, 18.6 ⁇ 0.2°, 19.1 ⁇ 0.2°, 20.2 ⁇ 0.2° and 28.0 ⁇ 0.2° 2 ⁇ (°), as determined by using Cu-K ⁇ radiation.
  • XRPD analysis is as shown in Figure 13 .
  • the X-ray powder diffraction pattern of the crystal form VI comprises characteristic peaks at 4.4 ⁇ 0.2°, 7.1 ⁇ 0.2°, 8.8 ⁇ 0.2°, 14.3 ⁇ 0.2°, 17.8 ⁇ 0.2°, 19.6 ⁇ 0.2° and 21.6 ⁇ 0.2° 2 ⁇ (°), and further comprises characteristic peaks at 25.5 ⁇ 0.2° and 27.7 ⁇ 0.2 2 ⁇ (°), as determined by using Cu-K ⁇ radiation.
  • XRPD analysis is as shown in Figure 14 .
  • the sulfate of the compound of formula (I) (1 g, 2.36 mmol, 1.0 eq) was dissolved in acetone (50 mL) for reflux; the mixture was stirred for 3 h, and a clear solution was not achieved by dissolving; heating was stopped; the solution was cooled down to room temperature and filtered by suction; and the filter cake was dried at 50°C to obtain the crystal form VI.
  • the X-ray powder diffraction pattern of the crystal form VI comprises characteristic peaks at 4.4 ⁇ 0.2°, 7.1 ⁇ 0.2°, 8.8 ⁇ 0.2°, 14.3 ⁇ 0.2°, 17.8 ⁇ 0.2°, 19.6 ⁇ 0.2° and 21.6 ⁇ 0.2° 2 ⁇ (°), and further comprises characteristic peaks at 25.5 ⁇ 0.2° and 27.7 ⁇ 0.2 2 ⁇ (°), as determined by using Cu-K ⁇ radiation.
  • XRPD analysis is as shown in Figure 15 .
  • the sulfate of the compound of formula (I) (1 g, 2.36 mmol, 1.0 eq) was dissolved in ethanol (15 mL) for reflux, and the mixture was stirred for 3 h; after the sulfate was dissolved to yield a clear solution, heating was stopped; the solution was cooled down to room temperature until a large number of solids were precipitated, and filtered by suction; and the filter cake was dried at 50°C to obtain the crystal form VI.
  • the X-ray powder diffraction pattern of the crystal form VI comprises characteristic peaks at 4.4 ⁇ 0.2°, 7.1 ⁇ 0.2°, 8.8 ⁇ 0.2°, 14.3 ⁇ 0.2°, 17.8 ⁇ 0.2°, 19.6 ⁇ 0.2° and 21.6 ⁇ 0.2° 2 ⁇ (°), and further comprises characteristic peaks at 25.5 ⁇ 0.2° and 27.7 ⁇ 0.2 2 ⁇ (°), as determined by using Cu-K ⁇ radiation.
  • XRPD analysis is as shown in Figure 16 .
  • the sulfate of the compound of formula (I) (1 g, 2.36 mmol, 1.0 eq) was dissolved in methanol (10 mL) for reflux, and the mixture was stirred for 3 h; after the sulfate was dissolved to yield a clear solution, heating was stopped; the solution was cooled down to room temperature until a large number of solids were precipitated, and filtered by suction; and the filter cake was dried at 50°C to obtain the crystal form VI.
  • the sulfate of the compound of formula (I) (1 g, 2.36 mmol, 1.0 eq) was dissolved in tetrahydrofuran (50 mL) for reflux, and the mixture was stirred for 3 h; in the case that a dissolved clarification of the reaction was not achieved, heating was stopped; the solution was cooled down to room temperature and filtered by suction; and the filter cake was dried at 50°C to obtain the crystal form VI.
  • the X-ray powder diffraction pattern of the crystal form VI comprises characteristic peaks at 4.4 ⁇ 0.2°, 7.1 ⁇ 0.2°, 8.8 ⁇ 0.2°, 14.3 ⁇ 0.2°, 17.8 ⁇ 0.2°, 19.6 ⁇ 0.2° and 21.6 ⁇ 0.2° 2 ⁇ (°), and further comprises characteristic peaks at 25.5 ⁇ 0.2° and 27.7 ⁇ 0.2 2 ⁇ (°), as determined by using Cu-K ⁇ radiation.
  • XRPD analysis is as shown in Figure 17 .
  • the sulfate of the compound of formula (I) (1 g, 2.36 mmol, 1.0 eq) was dissolved in isopropanol (50 mL) for reflux, and the mixture was stirred for 3 h; after the sulfate was dissolved to yield a clear solution, heating was stopped; the solution was cooled down to room temperature until a large number of solids were precipitated, and filtered by suction; and the filter cake was dried at 50°C to obtain the crystal form VII.
  • the X-ray powder diffraction pattern of the crystal form VII comprises characteristic peaks at 7.1 ⁇ 0.2°, 13.6 ⁇ 0.2°, 14.5 ⁇ 0.2°, 18.0 ⁇ 0.2°, 19.0 ⁇ 0.2°, 22.0 ⁇ 0.2° and 23.4 ⁇ 0.2° 2 ⁇ (°), and further comprises characteristic peaks at 15.0 ⁇ 0.2°, 16.1 ⁇ 0.2°, 17.4 ⁇ 0.2° and 19.4 ⁇ 0.2° 2 ⁇ (°), as determined by using Cu-K ⁇ radiation.
  • XRPD analysis is as shown in Figure 18 .
  • Test substances the compound of formula (I) was prepared by example 1 of the present invention, the crystal form I was prepared by example 2 of the present invention, and the crystal form II was prepared by example 16 of the present invention.
  • test substances using the solvent DMSO, the test substances were prepared into a 10 mM stock solution for long-term storage; the stock solution was diluted 100 times with DMSO to obtain a 100 ⁇ M working solution of the test substances; and the working solution of the compounds was diluted 3 times with DMSO to obtain a total of 8-10 concentration gradients of a diluted solution of the test substances (100 ⁇ ).
  • the diluted solution of the test substances was pipetted into a 384-well plate using Echo, a system for pipetting very small amount of liquid; to each test substance well, 200 nL of the diluted solution of the test substances and 10 ⁇ L of the PDE9A2 enzyme solution were added, and the plate was centrifuged at 1000 rpm for 1 min, and then incubated at room temperature for 15 min.
  • the instructions of the IMAP FP PDE Evaluation Kit (a kit for detecting enzyme activity), 10 ⁇ L of a substrate mixed liquor was added, and the mixture was centrifuged at 1000 rpm for 1 min and incubated with shaking at room temperature for 30 min.
  • Detection a microplate reader was used to detect the fluorescence reading (F) at 480 nm/535 nm.
  • Inhibition rate % FMax ⁇ F Compound FMax ⁇ FMin ⁇ 100 %
  • the compound of formula (I) for the experiment was dissolved with 2% DMSO + 10% PEG400 + 88% (28% HP- ⁇ -CD) physiological saline to prepare a solution; the solution of the test substance was administered to SD rats by gavage at a dose of 5.0 mg/kg; and the blood sampling time points were 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after administration.
  • the compound of formula (I) for the experiment was dissolved with 2% DMSO + 10% PEG400 + 88% (28% HP- ⁇ -CD) physiological saline to prepare a solution; the solution of the test substance was administered to SD rats by intravenous bolus at a dose of 1 mg/kg; and the blood sampling time points were 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after administration.
  • the crystal form I for the experiment was dissolved with 5% DMSO + 10% PEG400 + 85% (20% captisol) physiological saline solution to prepare a solution; the solution of the test substance was administered to SD rats by gavage at a dose of 60.0 mg/kg; and the blood sampling time points were 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 24 h, 30 h and 48 h after administration.
  • the crystal form I for the experiment was dissolved with 2% DMSO + 10% PEG400 + 88% (28% HP- ⁇ -CD) physiological saline to prepare a solution; the solution of the test substance was administered to SD rats by intravenous bolus at a dose of 5 mg/kg; and the blood sampling time points were 5 min, 15 min, 30 min, 1 h, 4 h, 8 h, 12 h and 24 h after administration.
  • Compound of formula (I) the ordinary SD rats were used and fixed; the tails of the rats were heated in a water bath 10 minutes before each time point; and about 100 ⁇ L of blood was collected via a tail vein, and then placed in an anticoagulation tube containing EDTA-K 2 .
  • the blood sample was centrifuged at 8000 rpm at 4°C for 6 min to obtain a plasma sample, which was prepared within 30 minutes after blood collection.
  • the plasma was stored in a refrigerator at -80°C before the test.
  • Crystal form I the rats were subjected to jugular vein cannulation (JVC); each time, about 0.35 ml of blood was collected from the rats via a jugular vein cannula into a centrifuge tube containing 5 ⁇ l of 15% EDTA-K2; the mixture was gently mixed to obtain a homogeneous mixture, and then the centrifuge tube was placed in an ice bath immediately. Within 1 hour after collecting whole blood, the mixture was centrifuged at 4°C and 2400 ⁇ g for 5 minutes, and the supernatant was immediately collected to obtain a plasma sample. The plasma was stored in a refrigerator at -80°C before the test.
  • JVC jugular vein cannulation
  • the plasma sample to be tested was taken out from the -80°C refrigerator, subjected to natural melting at room temperature, and then vortexed for 5 min; 20 ⁇ L of the plasma sample was precisely pipetted into a 1.5 mL centrifuge tube; 200 ⁇ L of the internal standard working solution (tolbutamide in methanol) at a concentration of 100 ng/mL was added, and the mixture was mixed homogeneously; the homogeneous mixture was vortexed for 5 min, and then centrifuged at 12000 rpm for 5 min; 50 ⁇ L of the supernatant was precisely pipetted into a 96-well plate pre-filled with 150 ⁇ L of water/well; and the plate was vortexed for 5 min for homogenization, and subjected to LC-MS/MS assay, with a sample loading volume of 5 ⁇ L.
  • the internal standard working solution tolbutamide in methanol
  • the plasma sample to be tested was taken out from the -80°C refrigerator, subjected to natural melting at room temperature, and then vortexed for about 30 seconds for homogenization; 50 ⁇ l of the sample (50 ⁇ l of the blank rat plasma collected for a blank sample and an internal standard blank sample) was pipetted into a 96-well plate (Plate-1); 20 ⁇ l of the IS-W solution was added [for the blank sample, 20 ⁇ l of methanol was added], and the mixture was mixed homogeneously; 400 ⁇ l of acetonitrile was added, and the mixture was vortexed for about 3 minutes with the 96-well plate covered with lid, and centrifuged at 3200 ⁇ g and 4°C for 5 minutes.
  • t z1/2 terminal elimination half-life
  • Cl _obs clearance rate
  • V z _obs apparent volume of distribution
  • T max time to reach peak plasma concentration
  • AUC last area under the plasma concentration-time curve from zero to infinity.
  • Test substances the crystal form I was prepared by example 2 of the present invention.
  • Test substances the compound of formula (I) was prepared by example 1 of the present invention, the crystal form I was prepared by example 2 of the present invention, the crystal form II was prepared by example 16 of the present invention, the crystal form I II was prepared by example 20 of the present invention, the crystal form IV was prepared by example 24 of the present invention, the crystal form V was prepared by example 25 of the present invention, the crystal form VI was prepared by example 27 of the present invention, and the crystal form VII was prepared by example 31 of the present invention.
  • hydrochloric acid solution at pH 1.0 9 ml of hydrochloric acid was pipetted, and water was added for dilution to 1000 ml; the mixture was mixed homogeneously to obtain a hydrochloric acid solution at pH 1.03.
  • Phosphate buffered solution at pH 4.5 1.56 g of sodium dihydrogen phosphate dihydrate was weighed, and 200 ml of water was added to obtain a phosphate buffered solution at pH 4.50.
  • each test substance was weighed, and 5 ml of the phosphate buffered solution (pH 4.5), 5 ml of the phosphate buffered solution (pH 6.8), and 5 ml of ultrapure water were added, respectively; the mixture was mixed homogeneously with shaking, and then placed in a 37°C water bath shaker for shaking; the samples were collected at 24 hours and subjected to centrifugation; and the supernatant was taken and directly injected (if the solubility was high, the supernatant was diluted with a 0.1 mol/L hydrochloric acid solution to an appropriate multiple and then injected).
  • the crystal form I was prepared by example 2 of the present invention
  • the crystal form II was prepared by example 16 of the present invention
  • the crystal form I II was prepared by example 20 of the present invention
  • the crystal form IV was prepared by example 24 of the present invention
  • the crystal form V was prepared by example 25 of the present invention
  • the crystal form VI was prepared by example 27 of the present invention
  • the crystal form VII was prepared by example 31 of the present invention.
  • Method the appropriate amount of different test substances were taken, and placed at 105°C for 3 days, and at 60°C and RH 92.5% under light for 5 days and 10 days, respectively; and the samples were collected on day 0, day 3, day 5 and day 10 to investigate the changes in the trait and content of the samples.
  • Table 5 and Table 6 show the results of the trait and content after placement at 105°C for 3 days.
  • Table 7 and Table 8 show the results of the trait and content after placement at 60°C and RH 92.5% under light for 5 days.
  • Table 9 and Table 10 show the results of the trait and content after placement at RH 92.5% under light for 10 days.
  • Table 5 Results of the trait of different test substances after placement for 3 days Test substances Trait 0 day Placed at 105°C for 3 days Crystal form II Yellow powder Yellow powder Crystal form III Yellow powder Yellow powder Crystal form VI Yellow powder Yellow powder Table 6 Results of the content of different test substances after placement for 3 days Test substances Content (%) 0 day Placed at 105°C for 3 days Crystal form II 99.8 99.5 Crystal form III 99.9 99.7 Crystal form VI 99.9 99.7

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WO2017019726A1 (fr) * 2015-07-29 2017-02-02 Merck Sharp & Dohme Corp. Oxy-cyanoquinolinone utilisée en tant qu'inhibiteur de pde9
CN109575016B (zh) * 2017-09-28 2022-01-04 药捷安康(南京)科技股份有限公司 Pde9抑制剂及其用途
CN107605187A (zh) * 2017-09-30 2018-01-19 伍京栋 一种可调节水温和水位的家庭儿童泳池
CN111471059B (zh) * 2019-01-23 2022-12-02 药捷安康(南京)科技股份有限公司 Pde9抑制剂及其用途

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AU2020242652A1 (en) 2021-10-28
JP2022534641A (ja) 2022-08-03
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KR20210138689A (ko) 2021-11-19
SG11202110055SA (en) 2021-10-28
CA3133717A1 (fr) 2020-09-24
CN111689958A (zh) 2020-09-22
TWI830884B (zh) 2024-02-01
TW202102496A (zh) 2021-01-16
US20220194934A1 (en) 2022-06-23
EP3939978A4 (fr) 2023-01-04
CN111689958B (zh) 2021-11-19
US20230125064A2 (en) 2023-04-20
CA3133717C (fr) 2023-12-05
ZA202107810B (en) 2022-08-31
AU2020242652B2 (en) 2023-02-23
JP7326662B2 (ja) 2023-08-16

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